Substituted lower fatty acid amides and processes



United States Patent 3,282,949 SUBSTITUTED LOWER FATTY ACID AMIDES ANDPROCESSES Leo Berger, Montclair, Alfred John Corraz, Packanack Lake, andJohn Lee, Montclair, N.J., assignors to Holimann-La Roche Inc., Nutley,NJ., a corporation of New Jersey No Drawing. Filed July. 3, 1963, Ser.No. 292,768

Claims. (Cl. 260-295) The present invention relates to substituted lowerfatty acid amides. More particularly, the present invention relates tosubstituted phenyl-N-(l,2,5,6-tetrahydro-l,3- di-lower alkyl-4-pyridyl)-lower fatty acid amides and to processes for their preparation.

The novel substituted lower fatty acid amides of the v invention havethe formula s (1) wherein R is hydrogen; halogen, e.g., fluorine,chlorine, or bromine, preferably chlorine; nitro; amino; lower 3,282,949Patented Nov. 1, 19 66 In the above reaction scheme R is hydrogen,halogen, e.g., F, Cl, Br, preferably chlorine, or nitro, and R R and nhave the meanings given above.

The above reaction can also be carried out using a nitrile in place of.the acid amide of Formula II, i.e., a compound of the formula employed,based on the weight of substituted amide or nitrile used. The phosphoricacid can be anhydrous, but preferably a small quantity of water ispresent, i.e., up to about 15 percent water, e.g., 85 percent phosphoricacid. The reaction is carried out at a temperature in alkylamino; phenyllower alkylamino; halo-substituted phenyl lower alkylamino; loweralkoxy-substituted phenyl lower alkylamino; and di-lower alkylamino; andR and whole number 1, 2 or 3.

Preferred compounds of Formula I are those wherein R is in thepara-position of the -(CH group. The invention also relates to acidaddition salts of the compounds of Formula I with pharmaceuticallyacceptable acids.

The compounds of Formula I and their acid addition salts exhibit bloodpressure-lowering activity and analgesic activity and are useful ashypotensive agents and as analgesics.

The compounds of Formula I wherein R is hydrogen, halogen, or nitro areprepared by reacting a substituted phenyl lower fatty acid amide of theformula I? (CHz)n-CNH:

R4 (II) with a substituted 4-piperidone of the formula [R2 i s in thepresence of either sulfuric acid or a mixture of phosphorus pentoxideand ortho-phosphoric acid, to form a compound of the formula I? (onus-carn the range of from about 50 to about 160, preferably from about toabout C. When sulfuric acid is employed, the sulfuric acid is preferablyanhydrous but can contain up to about 2 percent water. From Rs are loweralkyl groups, Preferably methyl; and n is the r about 0.85 to about 1.2parts by weight of sulfuric acid,

based on the weight of substituted amide or nitrile is usually employed.lWhen sulfuric acid is used an organic solvent, e.g., chloroform, ispreferably employed for carrying out the reaction. Other solvents thatcan be employed include carbon tetrachloride, methylene chloride,benzene, heptane, etc.

The compound of Formula IV is isolated from the above reaction mixtureby neutralizing the reaction mixture with alkali, preferably in aqueoussolution, which precipitates the product, and then removing the productfrom the neutralized aqueous solution, e.g., by filtration,

Compounds of Formula I wherein R is amino are prepared from a compoundof Formula IV wherein R is nitro according to the following reactionscheme:

( 2)n H2)n(|3=0 NH NH No, R,' NH, R:

I I R: R3

(V) (VI) wherein R R and n have the meanings given above.

The reduction of Compound V is carried out by treatment of Compound Vwith hydrogen 'in the presence of a hydrogenation-cata1lyst, e.g., PtOpalladium-on-charcoal, Raney nickel, rhodium-on carbon (or alumina),etc, preferably in the presence of,:a solvent, e.g., a lower alkano-l.

Compounds of Formula IV wherein R is a substitutedamino group areprepared by reacting a compound of Formula IV and an aldehyde to give aSchiffs base which is then reduced, for example, with hydrogen in thepresence of a hyclnogenation catalyst such as the above, or a groupI-group lI-I mixed metal hydride, sodium borohydride,

lowing reaction scheme:

' In the above reaction scheme R is hydrogen, an alkyl group having from1 to 6 carbon atoms, a phenyl group, or a haloor loweralk-oxy-substitu-ted phenyl group; and R and R have the meanings givenabove. Examples of aldehydes of'Formula V11 that can be employed includeformaldehyde, benzaldehyde, anisaldehyde, 3,4-dimethoxybenzaldehycle,parachlorobenzaldehyde, etc.

When atertiary amino group having a .lower alkyl group is desired, theabove reaction scheme is carried out a sec- 0nd time, using the compoundof the Formula 1X as the to give a compound of Formula XI wherein R ishydrogen or alkyl having from 1 to 6 carbon atoms, depending on thealdehyde of Formula VII chosen for the reaction. A The invention will bebetter understood by reference to the following examples which are.given for illustration purposes only. and are not meant to limit theinvention.

Example 1.Preparation of Z-phenyl--(I,2,5,6-tetrahydro-1,3-dimethyI-4-pyridyl)acetamide A solution of 70g. of phosphorus pentoxide in 70 g.

of percent phosphoric acid is prepared by placing the phosphoruspentoxide in a flask equipped with a stirrer, and adding the phosphoricacid thereto with caution. When the initial exothermic reaction subsides(the mixture heats up to a temperature of ZOO-250 C.) the mixture isheated externally (200-25 0) with constant stirring until a clearviscous solution is obtained. The solution is then cooledto roomtemperature with constant stirring. To the thick solution with constantstir-ring at room temperature are added 6.0 g. of phenylacetarnide and10.0 g. of 1,3-dirnethylpi-peridone-4 in that order. The mixture is thenheated to with constant stirring and kept at 100 for 10 hours. Water isadded to the reaction mixture and the insolnbles filtered off. Theacidic solution is made basic with sodium hydroxide flakes (cooling) andthe base that is obtained is crystallized with Skellysolve B and ethylacetate to yield the product, 2-phenyl-N-(l,2,5,6-tetrahydro-l,3-dimethyl-4-pyridyl)acetamide, M.P.- 142.

Example 2.Pre paration of 2-(4-nitr0phenyl) -N-(1,2,5,6,-tetrahydro-I,3-dimethyl-4-pyridyl)acetamide.

To a solution of'75 g. of phosphorus pentoxide in .75 g. of 85 percentphosphoric acid are added 20 g. of pnitrophenylacetamide and 20 g. of1,3-dimethylpiperidone- 4. The mixture is heated to 100 tor 10 hours,and then diluted with water. and the acidic solution made basic withstrong A solid base, 2-(4-nitropheny-l) N (1,2,5,6-tetrahydro-1,3-dirnethyl-4-pyridyl)acetamide, is obtained that melts at 162-164 whenrecrystallized from ethyl acetate.

Example 3.Preparati0n of 2-(4-aminophenyl)-N-(I,2, 5,6-tetrahydro-1,3-dimethyl-4 pyridyl acetamide catalyst filtered off through Hyflo: Thefiltrate is con-- centrated to dryness. The residue is dissolved in 50ml.

of water, excess potassium carbonateadded, and the base extracted withchloroform. The chloroform solution is dried over potassium carbonate,the desiccant filtered off, and the chloroform removed on a water bath.The residue is crystallized from a mixture of acetone and SkellysolveThe insoluble material is-filtered off.

There is no 5 B, to give the product, 2-(4-aminoph'enyl) N-i(1,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl)acetamide, M.P. 153- 154 (uncorn).Example 4.Preparatin of 2-(4-dimethylaminophenyl)- N-(l,2,5,6-tetrahydro1,3 dimethyl-4-pyridyl)-acetamide A mixture of 2-(4-nitropheny1)-N-(l,2,5,6-tetrahydro- 1,3-dimethyl-4-pyridyl)acetamide, 4 g. of 37percent form- Example 5 .--Preparation of 2-(4-benzylaminophenyl)-N- (1,2,5,6-tetrahydra-1,3-dimethyl-4-pyridyl) acetamide A mixture of 2 g. of2-(4 aminophenyl)-N-(1,2,5,6-tetrahydro-l,3-dirnethyl-4-pyridyl)acetamide and 0.8 g. of benzaldehydeis heated 1 hour on a steam bath. After the mixture cools to roomtemperature, 100 mg. of platinum oxide and 180 ml. of glacial aceticacid are added. The mixture is shaken in a Parr bomb under 3.6 atm. ofhydrogen at room temperature. Within 2 hours, the theoretical amount ofhydrogen is taken up and the reaction is stopped. The catalyst isfiltered off through Hyflo and the filtrate concentrated to drynessunder reduced pressure on a water bath. The residue is dissolved in 100ml. of water. Excess potassium carbonate is added and the mixtureextracted with chloroform. After the chloroform solution is dried overpotassium carbonate, the desiccant is filtered off and the solventremoved on a water bath. The residue is crystallized from Skellysolve Bto give the product, 2-(4-benzylaminophenyl) N(1,2,5,6-tetrahydro-1,3-dimethyl-4- yridyDacetamide, M.P. 101-105(uncorn).

Example 6.Preparati0n of 2-(4-chlor0pheny1)-N- (1,2,5,6-tetrahydr0-l ,3-dimethyl-4-pyridyl )acetamide A solution of 75 g. of phosphoruspentoxide in 75 g. of 85 percent phosphoric acid is prepared accordingto the process of Example 1. With constant stirring of the thicksolution, 20 g. of p-chlorophenylacetamide and 20 g. of1,3-dimethylpiperidone-4 are added and the mixture heated at 100 forhours. Water is then added and the insoluble material filtered off andthe acidic solution made basic with strong alkali.

The solid base that separates is filtered and air dried, M.P. 152-154".The base, 2-(4-chlorophenyl)-N-(1,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl)acetamide, is recrystallized fromacetone and melts at 156-157.

The base is converted to the hydrobromide with alcoholic HBr, M.P.165-172 (solvated) after recrystallization from acetone, and l84-186when dry.

Example 7.Preparation of 2-[4-(4-chlorobenzylamin0)phenyl]-N-(1,2,5,6-tetrahydro 1,3 dimethyl-4-pyridyl)acetamide A mixtureof 7 g. of 2-(4-aminophenyl)-N-(1,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl)acetamide, 200 ml. of benzene and 4 g.of p-chlorobenzaldehyde is refluxed and stirred for 6 hours. During thereaction, 0.5 ml. of water is removed by means of a Dean-Stark receivingtap. The mixture is cooled to +3, filtered and air dried, M.P. M.P.170-183". Following recrystallization from ethyl acetate, the M.P. is192-193. The Schifis base is dissolved in 180 ml. of glacial acetic acidand 0.2 g. of platinum oxide is added. The mixture is shaken in a Parrbomb under 3.7 atm. of hydrogen at room temperature. After 30 minutes,slightly more than the theoretical amount of hydrogen is taken up. Thereaction is stopped. Following the removal of the catalyst byfiltration, the acetic acid is removed under reduced pressure on a waterbath. The residue is dissolved in 200 ml. of water. Excess potassiumcarbonate is added and the mixture extracted with chloroform. After thechloroform solution is dried over sodium sulfate, the desiccant isfiltered off and the solvent removed on a water bath. Followingcrystallization of the residue with ethyl acetate, the product,2-[4-(4-chlorobenzylamino)phenyl]-N- (1,2,5,6-tetrahydro 1,3dimethyl-4-pyridyl) acetamide is obtained, M.P. 129.5-131". The smallportion is again recrystallized from ethyl acetate and the melting pointbecomes 130131.5.

Example 8.-Preparati0n of 2-[4-(3,4-dimethoxybenzylamino)phenyl]-N-(1,2,5,6-tetrahydro 1,3 dimethyl- 4-pyridyl)acetamide Amixture of 9 g. of 2-(4-aminophenyl)-N-(1,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl)acetamide, 200 ml. of benzene and 6 g.of 3,4-dimethoxybenzaldehyde is refluxed and stirred for 5 hours. Duringthe reaction, 1 mole of water is removed by means of a Dean-Starkreceiving tap. The volatile components are removed under reducedpressure and a small portion of the residue recrystallized from acetone,M.P. 156-157". The residue is dissolved in 150 ml. of methanol andheated to reflux with stirring. 4 g. of sodium borohydride dissolved in50 ml. of cold methanol is added as rapidly as the evolution of hydrogenfrom the reaction mixture permits. When the addition is over, thereaction mixture is refluxe and stirred for an additional hour, cooledto room temperature and decomposed with 20 ml. of water. Excess sodiumchloride is added and the mixture extracted with chloroform. After thechloroform solution is dried over sodium sulfate, the desiccant isfiltered off and the chloroform removed on a water bath. The residue isrecrystallized from acetone to give the product,2-[4-(3,4-dimethoxybenzylamino)phenyl] N (l,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl) acetamide, M.P. 138-142.

Example 9.Preparati0n of 2-(4-methylaminophenyl)-N-(1,2,5,6-tetrahydro-I,3-dimethyl-4-pyridyl)acetamide A mixture of 5 g.of2-(4-nitrophenyl)-N-(1,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl)acetamide,1.5 g. of 37 percent aqueous formaldehyde, /2 teaspoon of Raney nickeland enough methanol to bring the volume to 180 ml. are shaken in a Parrbomb under 3.5 atm. of hydrogen. The temperature is maintained near 76during the reaction. After 7 hours, slightly less than the theoreticalamount (4 moles) of hydrogen is taken up. The reaction is stopped. Whenthe reaction mixture cools to room temperature, the catalyst is filteredoff through Hyflo and the filtrate concentrated to dryness under reducedpressure on a water bath. The residue is crystallized from Skellysolve Bto give the product, 2-(4-methylaminophenyl)-N-(1,2,5,6-tetrahydro 1,3dimethyl-4-pyridyl)- acetamide, M.P. 94-96 (uncorn).

Example 10.Preparati0n of 3-phenyl-N-(1,2,5,6-tetrahydro-I,3-dimethyl-4-pyridyl)propionamide To a solution of 75 g. ofphosphorus pentoxide in 75 g. of percent phosphoric acid are added 20 g.of hydrocinnamonitrile and 20 g. of 1,3-dimethylpiperidone-4 and themixture heated with stirring for 10 hours at The cooled reaction mixtureis poured onto ice water and the insolubles filtered oil. The acidicsolution is made basic with strong alkali and the base that separates isdissolved in chloroform. The chloroform solution is dried, filtered froma drying agent, and concentrated to dryness. The residual base iscrystallized from ethyl acetate to give the product, 3phenyl-N-(l,2,5,6-tetrahydro-1,3-dimethyl-4-pyridyl)propionamide,melting at -117.

7 An additional quantity of product is recovered from the ethyl acetatemother liquors via concentration. Further recrystallization from ethylacetate does 'not alter the melting point.

Example 1I.Preparatz'=0n of 4-phenyl-N-(1,2,5,6-tetrahydro-I,3-dimethyl-4-pyridyl) butyramide line base,4-phenyl-N-(1,2,5,6-tetrahydro-1,3-dimethyl-4- pyridyl)butyramide,melting at 118-120. One recrystallization from ethyl acetate gave thepure base, melting at 118-120". We claim:

1. A compound of the formula NH NO wherein R and R are. lower alkylgroups and n isa whole number selected from the group consisting'of 1,2, and 3.

4. A compound of the formula NH NH wherein R and R are lower alkylgroups and n is a whole number selected from the group consisting of 1,2,'and 3.

5. A compound of the formula (CH2) n-(|3=O l NH R5CH=NH l wherein R andR are lower alkyl groups; R is selected from the group consisting 'ofhydrogen, an alkyl group having from 1 to 6 carbon atoms, phenyl,halo-substitutedphenyl, and lower alkoXy-substituted-phenyl; and n is awhole number selected from the group consisting of 1, 2 and 3.

6. A compound of the formula NH RsCHINH wherein R is selected from thegroup consisting of hydrogen, an alkyl group having from 1 to 6 carbonatoms, a phenyl group, or a haloor lower alkoxy-substitutedphenyl group;and n is a whole number selected from the group consisting of 1, 2, and3.

7; 2 (4 dimethylaminophenyl) N (1,2,5,6 tetrahydro-l,3-dimethyl-4-pyridyl) acetamide. 8. 2 (4 benzylaminophenyl) N (1,2,5,6tetrahydro-1,3-dimethyl-4-pyridyl)acetamide.

9. 2 (4 chlorophenyl) N (1,2,5,6 tetrahydro- 1,3-dimethyl-4-pyridylacetamide.

10. A process for preparing a compound of the formula wherein R and Rare lower alkyl groups; R is selected from the group consisting ofhydrogen, halogen, and nitro; and n is a whole number selected from thegroup consisting of 1, 2, and 3, comprising the steps of reacting acompound selected from the group consisting of (a) a compound of theformula (b) sulfuric acid, and isolating a compound of Formula I fromthe reaction mixture; wherein R R R and n in Formulas II, Ila,

III have the same meanings as in Formula IV.

(References on following page) i 9 10 References Cited by the ExaminerNoller, Chemistry of Organic Compounds, 2nd ed.,

UNI pp. 456, 457, 535, Saunders (1957).

TED STATES, PATENTS Royals, Advanced Organic Chemistry, 1st ed., p. 653,2,219,879 10/1940 Vanderbflt 260566 XR PIentice Ha11 1954 3,019,2621/1962 Ambela ng 260570.9 5

OTHER REFERENCES WALTER A. MODANCE, Primary Examiner.

Fieser and Fieser, Organic Chemistry, 3rd ed., pp. JOHN RANDOLPHExaminer 211, 600 Heath, 1958. A. L. ROTMAN, Assistant Examiner.

1. A COMPOUND OF THE FORMULA1-R3,3-R2,4-((4-R1-PHENYL)-(CH2)N-CO-NH-)-1,2,5,6TETRAHYDROPYRIDINEWHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN,NITRO, AMINO, LOWER ALKYLAMINO, PHENYLLOWER ALKYLAMINO,HALO-SUBSTITUTED-PHENYL-LOWER ALKYLAMINO, AMINO, LOWERALKOXY-SUBSTITUTED-PHENYL-LOWER ALKYLAMINO, AND DI-LOWER ALKYLAMINO; R2AND R3 ARE LOWER ALKYL GROUPS; AND N IS A WHOLE NUMBER SELECTED FROM THEGROUP CONSISTING OF 1, 2, AND 3.